Dataset Information

Aspartate potentiates tobramycin against multidrug-resistant Edwardsiella tarda through enhancing proton motive force and membrane permeability

ABSTRACT:

The antibiotic susceptibility/resistance of bacteria is influenced by their metabolic states. In tobramycin-resistant Edwardsiella tarda (LTB4-RToB), a dynamic metabolic state is observed, characterized by a general reduction in most metabolites as the minimum inhibitory concentration (MIC) increases. Among these, aspartate downregulation emerges as the most critical biomarker. Exogenous aspartate enhances the efficacy of tobramycin, enabling it to effectively kill both lab-evolved and clinically isolated multidrug-resistant (MDR) E. tarda, as demonstrated in an animal model. Aspartate increases intracellular tobramycin levels in a concentration- and time-dependent manner by promoting drug uptake. Metabolic reprogramming analysis of LTB4-RToB and clinically isolated MDR strain WY-28 reveals that exogenous aspartate restores downregulated metabolites, primarily enhancing alanine, aspartate, and glutamate metabolism; the pyruvate cycle; and glycine, serine, and threonine metabolism. These changes elevate the proton motive force and membrane permeability, thereby increasing tobramycin uptake. The resulting intracellular drug concentration surpasses the bactericidal threshold, effectively overcoming resistance in both LTB4-RroB and clinical MDR E. tarda. These findings identify aspartate as a potent metabolic reprogramming agent that potentiates aminoglycosides by boosting intracellular drug accumulation, offering a strategy to combat antibiotic-resistant E. tarda.

INSTRUMENT(S): Gas Chromatography MS - positive

PROVIDER: MTBLS12725 | MetaboLights | 2025-07-31

REPOSITORIES: MetaboLights

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			Action	DRS
	a_MTBLS12725_GC-MS_positive__metabolite_profiling.txt	Txt
	i_Investigation.txt	Txt
	m_MTBLS12725_GC-MS_positive__metabolite_profiling_v2_maf.tsv	Tabular
	s_MTBLS12725.txt	Txt

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Project description:The overuse of antibiotics has made public health and safety face a serious crisis. It is urgent to develop new clinical treatment methods to combat drug-resistant bacteria to alleviate the health crisis. The efficiency of antibiotics is closely related to the metabolic state of bacteria. However, studies on fluoroquinolone-resistant Salmonella are relatively rare. In this study, non-targeted metabolomics was used to analyze the metabolic difference between sarafloxacin-susceptible Salmonella Typhimurium (SAR-S) and sarafloxacin-resistant Salmonella Typhimurium (SAR-R), and found that the central carbon metabolism was weakened due to drug resistance. We also confirmed that exogenous L-leucine increased the killing effect of sarafloxacin on SAR-R and other clinically resistant Salmonella serotypes. Exogenous L-leucine stimulated the metabolic state of bacteria, especially the TCA cycle, which increased the working efficiency of the electron transfer chain and increased the intracellular NADH, ATP concentration and reactive oxygen species level. Furthermore, we used real-time quantitative PCR to confirm the changes in various metabolic characteristics. Our results suggest that when the metabolism of drug-resistant bacteria is reprogrammed, the bactericidal effect of antibiotics improves. This study further enhances research in the anti-drug resistance field at the metabolic level and provides theoretical support for solving the current problem of sarafloxacin drug resistance, a unique fluoroquinolone drug for animals. To sum up, our research results showed that exogenous L-leucine promotes the bactericidal effect of antibiotics through metabolic modification of drug-resistant bacteria, which has the potential as a new adjuvant of antibiotics. LC-MS negative mode is reported in the current study <a href='https://www.ebi.ac.uk/metabolights/MTBLS7713' rel='noopener noreferrer' target='_blank'>MTBLS7713</a>.LC-MS positive mode is reported in <a href='https://www.ebi.ac.uk/metabolights/MTBLS7711' rel='noopener noreferrer' target='_blank'>MTBLS7711</a>.

Project description:The overuse of antibiotics has made public health and safety face a serious crisis. It is urgent to develop new clinical treatment methods to combat drug-resistant bacteria to alleviate the health crisis. The efficiency of antibiotics is closely related to the metabolic state of bacteria. However, studies on fluoroquinolone-resistant Salmonella are relatively rare. In this study, non-targeted metabolomics was used to analyze the metabolic difference between sarafloxacin-susceptible Salmonella Typhimurium (SAR-S) and sarafloxacin-resistant Salmonella Typhimurium (SAR-R), and found that the central carbon metabolism was weakened due to drug resistance. We also confirmed that exogenous L-leucine increased the killing effect of sarafloxacin on SAR-R and other clinically resistant Salmonella serotypes. Exogenous L-leucine stimulated the metabolic state of bacteria, especially the TCA cycle, which increased the working efficiency of the electron transfer chain and increased the intracellular NADH, ATP concentrationa nd reactive oxygen species level. Furthermore, we used real-time quantitative PCR to confirm the changes in various metabolic characteristics. Our results suggest that when the metabolism of drug-resistant bacteria is reprogrammed, the bactericidal effect of antibiotics improves. This study further enhances research in the anti-drug resistance field at the metabolic level and provides theoretical support for solving the current problem of sarafloxacin drug resistance, a unique fluoroquinolone drug for animals. To sum up, our research results showed that exogenous L-leucine promotes the bactericidal effect of antibiotics through metabolic modification of drug-resistant bacteria, which has the potential as a new adjuvant of antibiotics. LC-MS positive mode is reported in the current study <a href='https://www.ebi.ac.uk/metabolights/MTBLS7711' rel='noopener noreferrer' target='_blank'>MTBLS7711</a>.LC-MS negative mode is reported in <a href='https://www.ebi.ac.uk/metabolights/MTBLS7713' rel='noopener noreferrer' target='_blank'>MTBLS7713</a>.

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Aspartate potentiates tobramycin against multidrug-resistant Edwardsiella tarda through enhancing proton motive force and membrane permeability

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